glycyl-prolyl-glutamic-acid and Brain-Injuries

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.

Topics: Animals; Brain Injuries; Brain Ischemia; Disease Models, Animal; Humans; Insulin-Like Growth Factor I; Oligopeptides; Peptide Fragments

Glycine-proline-glutamate (GPE) is an N-terminal tripeptide endogenously cleaved from insulin-like growth factor-1 in the brain and is neuroprotective against hypoxic-ischemic brain injury and neurodegeneration. NNZ-2566 is an analog of GPE designed to have improved bioavailability. In this study, we tested NNZ-2566 in a rat model of penetrating ballistic-type brain injury (PBBI) and assessed its effects on injury-induced histopathology, behavioral deficits, and molecular and cellular events associated with inflammation and apoptosis. In the initial dose-response experiments, NNZ-2566 (0.01-3 mg/kg/h x 12 h intravenous infusion) was given at 30 min post-injury and the therapeutic time window was established by delaying treatments 2-4 h post-injury, but with the addition of a 10- or 30-mg/kg bolus dose. All animals survived 72 h. Neuroprotection was evaluated by balance beam testing and histopathology. The effects of NNZ-2566 on injury-induced changes in Bax and Bcl-2 proteins, activated microgliosis, neutrophil infiltration, and astrocyte reactivity were also examined. Behavioral results demonstrated that NNZ-2566 dose-dependently reduced foot faults by 19-66% after acute treatments, and 35-55% after delayed treatments. Although gross lesion volume was not affected, NNZ-2566 treatment significantly attenuated neutrophil infiltration and reduced the number of activated microglial cells in the peri-lesion regions of the PBBI. PBBI induced a significant upregulation in Bax expression (36%) and a concomitant downregulation in Bcl-2 expression (33%), both of which were significantly reversed by NNZ-2566. Collectively, these results demonstrated that NNZ-2566 treatment promoted functional recovery following PBBI, an effect related to the modulation of injury-induced neural inflammatory and apoptotic mechanisms.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Apoptosis Regulatory Proteins; Astrocytes; Brain; Brain Injuries; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Gliosis; Injections, Intravenous; Microglia; Movement Disorders; Nerve Degeneration; Neuroprotective Agents; Oligopeptides; Rats; Rats, Sprague-Dawley; Recovery of Function; Treatment Outcome